Drug delivery systems and methods for treatment of prostate

ABSTRACT

Methods, devices, and medicaments that include a drug are provided for use in the treatment of the prostate by locally administering the drug into the bladder of a patient to achieve a sustained concentration of the drug in urine in the bladder sufficient to produce a therapeutic concentration of the drug in the prostate. The drug may be delivered into the bladder from an intravesical drug delivery device inserted into the bladder, wherein the device continuously releases the drug into the urine in the bladder over an extended period of hours or days.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 14/628,874,filed Feb. 23, 2015, now U.S. Pat. No. 9,636,488, which is acontinuation of PCT/US2013/057841, filed Sep. 3, 2013, which claims thebenefit of U.S. Provisional Patent Application No. 61/696,029, filedAug. 31, 2012, which are incorporated herein by reference.

BACKGROUND

Delivery of diagnostic or therapeutic agents to the prostate isdifficult. Current practice requires systemic administration, such as byintravenous, intramuscular, oral, transdermal, or intranasal routes,using doses which result in significant exposure to healthy tissues andrelatively low exposure within the prostate gland. Frequently thesystemic exposure leads to unwanted or harmful side effects which limitthe usefulness of the therapeutic agent in treating prostate disease.

Targeted and local delivery strategies have been explored to minimizeperipheral exposure with limited success. Some targeting strategies relyon prostate cells to express specific receptors to which adrug-targeting ligand complex binds. These receptors may not always bepresent, limiting the utility of the approach. The receptor density onprostate cells also can vary widely and restrict the actual amount ofdrug delivered to the prostate. In addition, other cells in the body mayalso express the same receptor leading to unwanted drug exposure.Lastly, the drug targeting ligand complex can be degraded prior toreaching the prostate, defeating the targeting mechanism.

Direct injection into or near the prostate also has been tried. Patientacceptance is low due to the pain and risk of infection. In addition,the mean residence time of the drug often is relatively short, whichnecessitates the use of multiple injections for treatment. Furthermore,the disruption of prostate tumors during injection can lead tometastasis. Depot formulations extend the drug presence in the prostatebut reduce the amount of drug that can be injected into the prostate andmay enhance local tissue toxicity.

Radionucleotide-containing pellets placed near the prostate are used totreat prostate cancer but provide only one treatment modality. Radiationtherapy is also non-selective, leading to significant damage tosurrounding healthy tissue structures including nerves.

The use of a suppository or drug eluting stent placed in the prostaticurethra is known, but these are difficult to place and poorly toleratedin men. Furthermore, these delivery means have a limited payloadcapacity.

Accordingly, there remains a need for improved drug delivery methods andsystems for treating the prostate, such as in the treatment of prostatecancer or prostatitis.

SUMMARY

In one aspect, a medicament is provided that includes gemcitabine foruse in the treatment of the prostate by locally administering thegemcitabine into the bladder of a patient to achieve a sustainedconcentration of the drug in the urine in the bladder sufficient toproduce a therapeutic concentration of the drug in the prostate, whereinthe locally administering into the patient's bladder is at a meanaverage amount of from 1 mg to about 300 mg per day. The locallyadministering of gemcitabine may be continuous or intermittent. In oneembodiment, the patient is in need of treatment for prostate cancer. Inan embodiment, the gemcitabine is delivered into the bladder from anintravesical drug delivery device which continuously releases thegemcitabine into the urine in the bladder over a sustained period. In analternative embodiment, the gemcitabine is delivered into the bladderfrom a coating substance applied to the bladder, which coating substancecontinuously releases the gemcitabine into the urine in the bladder overa sustained period. The coating substance may include a mucoadhesiveformulation. In a further alternative embodiment, a liquid form of thegemcitabine is pumped into the bladder through a urethral catheterinserted into the bladder. In various embodiments, the gemcitabine isreleased into the patient's bladder continuously over a period of atleast 2 hours, such as from 1 day to 14 days. In an embodiment, thegemcitabine is released into the patient's bladder at a mean averageamount of from 1 mg to about 100 mg gemcitabine per day for up to 7days. In another embodiment, the gemcitabine is released into thepatient's bladder at a mean average amount of from 20 mg to 300 mg perday for up to 7 days.

In another aspect, a medical device is provided for intravesicaladministration of gemcitabine. In an embodiment, the medical deviceincludes a housing configured for intravesical insertion and a dosageform including gemcitabine, wherein the housing holds the dosage formand is configured to release the gemcitabine into the bladder in anamount therapeutically effective for the treatment of the prostate, andwherein the device is configured to release gemcitabine into the bladderat a mean average amount of from 1 mg to about 300 mg per day of thegemcitabine. The gemcitabine contained in the housing may be in anon-liquid form. The housing may be elastically deformable between aretention shape configured to retain the device in a patient's bladderand a deployment shape for passage of the device through the patient'surethra. In an embodiment, the device is configured to release from 1 mgto 100 mg of gemcitabine per day for up to 7 days. In anotherembodiment, the device is configured to release from 20 mg to 300 mg ofgemcitabine per day for up to 7 days.

In still another aspect, a method is provided of administering a drug toa patient in need of treatment of the prostate. The method includeslocally administering gemcitabine into the bladder of a patient toachieve a sustained concentration of the gemcitabine in urine in thebladder sufficient to produce a therapeutic concentration of thegemcitabine in the prostate. In one embodiment, the method includesadministering at least a second therapeutic agent to the patient. Thesecond therapeutic agent may be administered intravesically. The secondtherapeutic agent may include a cytotoxic agent, an analgesic agent, ananti-inflammatory agent, or a combination thereof. The secondtherapeutic agent may prevent, treat, or ameliorate cystitis of thebladder.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B illustrate one embodiment of an intravesical drug deliverydevice that may be used for administering gemcitabine as describedherein.

FIGS. 2A-2B illustrate another embodiment of an intravesical drugdelivery device that may be used for administering gemcitabine asdescribed herein.

FIGS. 3A-3C illustrate still another embodiment of an intravesical drugdelivery device that may be used for administering gemcitabine asdescribed herein.

FIGS. 4A-4B illustrate a method of inserting an intravesical drugdelivery device into the bladder of a patient for local administrationof gemcitabine as described herein.

FIG. 5A illustrates a material applied to the inner surface of thebladder wall for local administration of gemcitabine as describedherein.

FIG. 5B illustrates a method of applying a coating material onto to theinner surface of the bladder wall for local administration ofgemcitabine as described herein.

FIG. 6 illustrates a method of applying a liquid drug or drugformulation into the bladder.

FIG. 7 illustrates the concentration of gemcitabine in the prostateafter bladder perfusion and intravenous administration.

FIG. 8 illustrates the plasma levels of gemcitabine after bladderperfusion and intravenous administration.

FIG. 9 illustrates ¹⁴C gemcitabine concentration in the bladder afterbladder perfusion and intravenous administration.

FIG. 10 illustrates oxaliplatin terminal concentrations after bladderperfusion.

FIG. 11 illustrates cisplatin terminal concentrations after bladderperfusion and intravenous administration.

DETAILED DESCRIPTION

It has been discovered that intravesical administration can be used todeliver a therapeutically effective amount of gemcitabine to a patient'sprostate over a short or extended period while minimizing systemicexposure of the drug. For example, a controlled amount of drug may bedissolved in urine in the patient's bladder in a concentration and overa time sufficient to produce therapeutic concentrations of the drug inthe prostate. Because the bladder limits the absorption of urinecomponents into the general circulation, systemic exposure to the drugis advantageously minimized.

A variety of methods can be used to achieve the required urineconcentrations of the gemcitabine. In one embodiment, the drug can beprovided by direct instillation of a simple solution into the bladder.For example, a solution of the drug may be pumped into the bladderthrough a urethral or suprapubic catheter in a continuous or pulsatilemanner over the treatment period. In another embodiment, the drug isreleased from a device or composition deployed in the bladder, whereinthe device or composition releases the drug (continuously orintermittently) at a rate effective to produce the desired concentrationof drug in the urine over a specified treatment period. For example, thedrug may be released from an intravesically-inserted device into thebladder and then the drug diffuses from the bladder to the prostate. Atthe end of the treatment period, the device may be retrieved from thebladder, or it may be eliminated by being resorbed, dissolved, excreted,or a combination thereof.

In a preferred embodiment, the drug is gemcitabine, which is effectivein treating prostate cancer. The therapeutic utility of gemcitabine totreat prostate diseases is thought to be the result of the uniquecombination of the compound's physical and chemical properties whichfacilitate prostate uptake following intravesical administration andhigh intrinsic drug potency toward prostate tumor cells. See Examplesbelow.

In other embodiments, the drug may be essentially any suitable drug,including but not limited to ones useful in the treatment of prostatecancer, benign prostatic hyperplasia, or prostatitis. For example, thedrug may be an antibiotic, an alpha blocker, an anti-inflammatory, analpha 1A antiadrenergic, an antiandrogen, a microtubule inhibitor, or a5 alpha reductase inhibitor. Examples of other drugs include but are notlimited to ciproflaxin, trimethoprim, docetaxel, and finasteride.

In a preferred embodiment, the drug is administered to the prostate froman intravesical device. Preferred examples of intravesical drug deliverydevices and methods of deploying those devices into the bladder aredescribed in the following U.S. Patent Application Publications: US2012/0203203 (Lee et al.); US 2012/0089122 (Lee et al.); US 2012/0089121(Lee et al.); US 2011/0218488 (Boyko et al.); US 2011/0202036 (Boyko etal.); US 2011/0152839 (Cima et al.); US 2011/0060309 (Lee et al.); US2010/0331770 (Lee et al.); US 2010/0330149 (Daniel et al.); US2010/0003297 (Tobias et al.); US 2009/0149833 (Cima et al.); and US2007/0202151 (Lee et al.).

In embodiments in which the drug is delivered from an intravesical drugdelivery device, the drug may be housed in the device in various forms,which may depend on the particular mechanism by which the devicecontrollably releases the drug into fluid (e.g., urine) in the bladder.In some embodiments, the drug is provided in a solid, semi-solid, orother non-liquid form, which advantageously may facilitate stablestorage of the drug before the device is used and advantageously mayenable the drug payload of the device to be stored in smaller volumethan would be possible if the drug were housed in the form of a liquidsolution. In an embodiment the non-liquid form is selected from tablets,granules, semisolids, capsules, and combinations thereof. In oneembodiment, the drug is in the form of a plurality of tablets, such asmini-tablets described in U.S. Pat. No. 8,343,516. In other embodiments,the drug may be housed in a liquid form, such as in a solution with apharmaceutically acceptable excipient.

An embodiment of a drug delivery device 100 is illustrated in FIG. 1A.The device 100 includes a device body having a drug reservoir portion102 and a retention frame portion 104. In FIG. 1, the device 100 isshown in a relatively expanded shape suited for retention in the body.Following deployment into the body, the device 100 may assume therelatively expanded shape to retain the drug delivery device in the bodycavity or lumen.

For the purposes of this disclosure, terms such as “relatively expandedshape”, “relatively higher-profile shape”, or “retention shape”generally denote any shape suited for retaining the device in theintended implantation location, including but not limited to the pretzelshape shown in FIG. 1 that is suited for retaining the device in thebladder. Similarly, terms such as “relatively lower-profile shape” or“deployment shape” generally denote any shape suited for deploying thedrug delivery device into the body, including a linear or elongatedshape that is suited for deploying the device through the workingchannel of catheter, cystoscope, or other deployment instrumentpositioned in the urethra. In embodiments, the drug delivery device maynaturally assume the relatively expanded shape and may be deformed,either manually or with the aid of an external apparatus, into therelatively lower-profile shape for insertion into the body. Oncedeployed the device may spontaneously or naturally return to theinitial, relatively expanded shape for retention in the body.

In the illustrated embodiment, the drug reservoir and retention frameportions 102, 104 of the drug delivery device 100 are longitudinallyaligned and are coupled to each other along their length, although otherconfigurations are possible. The drug delivery device 100 includes anelastic or flexible device body 106 that defines a drug reservoir lumen108 (i.e., the drug housing) and a retention frame lumen 110. The drugreservoir lumen 108 is designed to house a drug formulation thatcomprises the drug. In the illustrated embodiment, the drug formulationis in the form of a number of solid drug tablets 112. The retentionframe lumen 110 is designed to house a retention frame 114 to form theretention frame portion 104. The illustrated lumens 108, 110 arediscrete from each other, although other configurations are possible.

As shown in the cross-sectional view of FIG. 1B, the device body 106includes a tube or wall 122 that defines the drug reservoir lumen 108and a tube or wall 124 that defines the retention frame lumen 110. Thetubes 122, 124 and lumens 108, 110 can be substantially cylindrical,with the drug reservoir lumen 108 having a relatively larger diameterthan the retention frame lumen 110, although other configurations can beselected based on, for example, the amount of drug to be delivered, thediameter of the retention frame, and deployment considerations such asthe inner diameter of the deployment instrument. The wall 124 thatdefines the retention frame lumen 110 may extend along the entire lengthof the wall 122 that defines the drug reservoir lumen 108, so that theretention frame lumen 110 has the same length as the drug reservoirlumen 108 as shown, although one wall may be shorter than the other wallin other embodiments. The two walls 122, 124 are attached along theentire length of the device in the illustrated embodiment, althoughintermittent attachment can be employed.

As shown in FIG. 1A, the drug reservoir lumen 108 is loaded with anumber of drug units 112 in a serial arrangement. Essentially any numberof drug units may be used, for example, depending upon the sizes of thereservoir and the drug units. The drug reservoir lumen 108 includes afirst end opening 130 and an opposed second end opening 132. Once thedrug units 112 are loaded, restraining plugs 120 are disposed in theopenings 130 and 132. The restraining plugs 120, in this embodiment, arecylindrical plugs secured into the entry 130 and the exit 132. In otherembodiments, the openings 130 and 132 are closed off with otherstructures or materials, which may, depending on the particularembodiments, include an aperture or a water- or drug-permeable wall tofacilitate ingress or egress of water or drug during use.

The retention frame lumen 110 is loaded with the retention frame 114,which may be an elastic wire. The retention frame 110 may be configuredto return spontaneously to a retention shape, such as the illustratedexample “pretzel” shape or another coiled shape, such as those disclosedin the applications previously incorporated. In particular, theretention frame 114 may retain the device 100 in the body, such as inthe bladder. For example, the retention frame 114 may have an elasticlimit and modulus that allows the device 100 to be introduced into thebody in a relatively lower-profile shape, permits the device 100 toreturn to the relatively expanded shape once inside the body, andimpedes the device from assuming the relatively lower-profile shapewithin the body in response to expected forces, such as the hydrodynamicforces associated with contraction of the detrusor muscle and urination.Thus, the device 100 may be retained in the body once implanted,limiting or prevent accidental expulsion.

The material used to form the device body 106, at least in part, may beelastic or flexible to permit moving the device 100 between deploymentand retention shapes. When the device is in the retention shape, theretention frame portion 104 may tend to lie inside the drug reservoirportion 102 as shown, although the retention frame portion 104 can bepositioned inside, outside, above, or below the drug reservoir portion102 in other cases.

The material used to form the device body 106 may be water permeable sothat solubilizing fluid (e.g., urine or other bodily fluid) can enterthe drug reservoir portion 102 to solubilize the drug units 112 once thedevice is implanted. For example, silicone or another biocompatibleelastomeric material may be used. In other embodiments, the device bodymay be formed, at least in part, of a water-impermeable material.

FIG. 2A illustrates an implantable drug delivery device 200, whichincludes a drug reservoir 202 loaded with drug 212 and a retentionstructure that includes two filaments 220, 222 associated with afastener 230. As shown, the drug reservoir 202 is an elongated tube thatcan be deformed between a relatively linear deployment shape, such asthe shape shown in FIG. 2A, and a relatively circular retention shape,such as the shape shown in FIG. 2B. The drug 212 may be loaded in thetube in a flexible form, so that the drug reservoir 102 can be movedbetween the two shapes. For example, the drug 212 may be a number ofsolid drug tablets, a liquid, or a gel. The filaments 220, 222 may beattached to opposite ends of the drug reservoir 202 and joined by thefastener 230. The fastener 230 can be adjusted to adjust the position ofone filament 220 with reference to the other 222, thereby adjusting theposition of one end of the drug reservoir 202 with reference to theother end. The device 200 can assume the retention shape by adjustingthe filaments 220, 222 to draw the ends of the drug reservoir 202 closertogether, and thereafter the device 200 can be retained in the retentionshape by preventing adjustment of the filaments 220, 222 with thefastener 230. In such an embodiment, the device 200 is manually adjustedinto the retention shape by manually adjusting the filaments 220, 222after the device 200 is inserted into the bladder.

In the illustrated embodiment, the fastener 230 is a cinch nut thatpermits shortening the portion of the filaments 220, 222 between thedrug reservoir ends and the cinch nut, but prevents lengthening of theseportions of the filaments 220, 222. Thus, the ends of the drug reservoir202 can be drawn closer together by pulling one or both of the filaments220, 222 through the cinch nut, causing the device 200 to assume theretention shape. Once the filaments 220, 222 have been so adjusted, thecinch nut prevents lengthening of the filaments 220, 222, retaining thedevice in the retention shape. Thus, manually adjusting the device 200into the retention shape once implanted merely requires pulling one orboth of the filaments 220, 222, although other fasteners 230 thatrequire separate manipulation can be employed. Other fasteners may alsobe used.

Another embodiment of an intravesical drug delivery device isillustrated in FIGS. 3A-3C. In this embodiment, the device includes ahousing 300 having a single, continuous structure with multiple,discrete drug reservoir lumens 320 and optionally having at least oneretention frame lumen 330 in which a retention frame 360 is disposed.Each drug reservoir lumen 320 has two defined openings, as shown in FIG.3B, and is dimensioned to hold at least one solid drug unit 340. Soliddrug unit 340 may be a drug tablet or capsule. In other embodiments notshown, each drug reservoir lumen has one defined opening. The housingmay be formed of a flexible polymer, such as silicone. FIG. 3B is across-sectional view of the plane that bisects one of the drug reservoirlumens 320 of the housing shown in FIG. 3A along line 3B-3B. As shown inFIG. 3B, the monolithic housing 300 has two defined openings (350 a, 350b) in its drug reservoir lumen 320 that expose both ends of the soliddrug unit 340. The retention frame lumen 330, in this embodiment, isaligned parallel to the longitudinal axis of the housing andperpendicular to the drug reservoir lumen 320. FIG. 3C is a perspectiveview of a portion of the embodiment of the device 300 shown in FIG. 3Awhen the device is in its retention shape, which is taken when theretention frame 360 is disposed in the retention frame lumen 330. Thedrug reservoir lumens 320 and the retention frame 360 in the housing ofthis embodiment are oriented so that the drug reservoir lumens 320 areoutside the retention frame's 360 arc. Alternatively, the housing inFIG. 3C can be rotated 180 degrees about the retention frame 360 toyield a configuration in which the drug reservoir lumens 320 arearranged within the retention frame's 360 arc. With this embodiment, thedevices provide sufficient direct contact between solid drug units andwith urine surrounding the device when deployed and retained in thebladder. In embodiments, release of the drug from the device iscontrolled by erosion of an exposed portion of the surface of a soliddrug unit, such that the rate of drug release from the drug deliverydevice may be directly proportional to and limited by the total exposedsurface area of the solid drug units.

One embodiment of inserting an intravesical device 400 for subsequentcontrolled release of the drug into the bladder is shown in FIGS. 4A and4B. Here, the device 400 is shown assuming a retention shape as thedevice exits a deployment instrument 402. The deployment instrument 402may be any suitable device. It may be a lumenal device, such as acatheter, urethral catheter, or cystoscope. The deployment instrument402 may be a commercially available device or a device specially adaptedfor the present drug delivery devices. FIG. 4B illustrates the insertionof the device 400 into the bladder, wherein the adult male anatomy isshown by way of example. The deployment instrument 402 is insertedthrough the urethra to the bladder, and the device 400 may be passedfrom/through the deployment instrument 402, driven by a stylet or flowof lubricant or combination thereof until the device 400 exits into thebladder, and as shown is in a retention shape.

In various embodiments, the drug may be released from the intravesicaldrug delivery device by diffusion to through a wall of the drug housing,by diffusion to through one or more defined apertures in a wall of thedrug housing, by osmotic pressure through an aperture in the drughousing, by erosion of a drug formulation in contact with urine in thebladder, or by a combination thereof.

In some embodiments in which the device comprises a drug in a solidform, elution of drug from the device occurs following dissolution ofthe drug within the device. Bodily fluid enters the device, contacts thedrug and solubilizes the drug, and thereafter the dissolved drugdiffuses from the device or flows from the device under osmotic pressureor via diffusion. For example, the drug may be solubilized upon contactwith urine in cases in which the device is implanted in the bladder.

In various embodiments, the intravesical device may release the drugcontinuously or intermittent to achieve a concentration of the drug inthe bladder that produces a sustained, therapeutically effectiveconcentration of the drug in the prostate over a period from 1 hour to 1month, for example from 2 hours to 2 weeks, from 6 hours to 1 week, from24 hours to 72 hours, etc.

In various embodiments, the intravesical device may release thegemcitabine or other drug in an amount of from 1 mg/day to 100 mg/day,for example from 20 mg/day to 300 mg/day or from 25 mg/day to 300mg/day.

In another embodiment, a coating substance may be intravesically appliedto the bladder wall, wherein the coating substance includes thegemcitabine or other drug and one or more excipient materials thatpromote adherance of the coating substance to the bladder wall andprovides continuous controlled release of the drug over the treatmentperiod. The coating substance may be a mucoadhesive formulation, such asgels, ointments, creams, films, emulsion gels, tablets, polymers, or acombination thereof. Mucoadhesive formulation polymers may includehydrogels or hydrophilic polymers, polycarbophil (i.e. Carbopols, etc.),chitosan, polyvinylpyrrolidone (PVP), lectin, polyethyleneglycolatedpolymers, celluloses, or a combination thereof. Suitable cellulosesinclude methyl cellulose (MC), carboxymethyl cellulose (CMC),hydroxypropyl cellulose (HPC), or combinations thereof. The coatingsubstance may include a permeation enhancer. Non-limiting examples ofpermeation enhancers include dimethyl sulfoxide (DMSO), sodiumcarboxymethyl cellulose (NaCMC), lipids, surfactants, or combinationsthereof. As shown in FIG. 5A, a coating substance 500 may be deployed inthe bladder 550 so that the coating substance 500 engages the bladderwall 552.

The coating substance may be deployed in the bladder using a deploymentinstrument. FIG. 5B is a sagittal view of a male genitourinary system,illustrating a coating substance 500 being deployed through a deploymentinstrument 502 into an implantation site. By way of example, the maleanatomy is shown and the implantation site is shown as the bladder 550.The coating substance 500 may be an embodiment of one of the coatingsubstances described herein. The deployment instrument 502 may be anydevice designed to navigate natural lumens of the body to reach theintended implantation site. For deployment in the bladder 550, thedeployment instrument 502 is sized and shaped for passing through aurethra 560 of a patient to a bladder 550 as shown. The deploymentinstrument 502 may be a known device, such as a catheter or cystoscope,or a specially designed device. The deployment instrument 502 is used todeploy the coating substance 500 into the body and is subsequentlyremoved from the body, leaving the coating substance 500 whollyimplanted in the body. Once so implanted, the coating substance 500 mayrelease drug into the body for an extended period. A comparableprocedure can be used to deploy any of the devices or drugs describedherein into other parts of the body through other natural lumens. Forexample, as shown in FIG. 6, a deployment instrument 602 can be used todeploy a liquid drug or drug formulation 600 into the bladder 650 bypassing the deployment instrument 602 through a urethra 660.

In one embodiment, a second therapeutic agent is administered to thepatient. The second therapeutic agent may be administeredintravesically. The methods and systems described herein may be used toadminister the second therapeutic agent intravesically. The secondtherapeutic agent may include a cytotoxic agent, an analgesic agent, ananti-inflammatory agent, or a combination thereof. In one embodiment,the second therapeutic agent prevents, treats, or ameliorates cystitisof the bladder.

The intravesical methods and systems described herein also may be usedto deliver therapeutic concentrations to bladder-regional tissuesbesides the prostate. For example, maintaining a drug urineconcentration at a certain level may achieve therapeutic concentrationsof drug in the ureters, kidneys, urethra, lower portions of theperitoneum, regional lymph nodes, uterus, ovaries, distal portions oflarge bowel, including the rectum and pelvic floor musculature.

The term “patient” as used herein refers to humans or other mammals,such as in veterinary or livestock applications. In a particularembodiment, the patient is an adult human male.

The present invention may be further understood with reference to thefollowing non-limiting examples.

Example 1: Gemcitabine Prostate Uptake from Bladder

A study was conducted on male Sprague Dawley rats administering ¹⁴Cgemcitabine by intra-urinary bladder cannula, over a 6- or 24-hourcontinuous perfusion, or by a single IV bolus. The 6- and 24-hourcontinuous perfusions perfused 6.9 and 26.6 mg, respectively, ofgemcitabine into the bladder. The single IV bolus included 5.0 mg ofgemcitabine.

Blood (FIG. 8), urine, and tissue samples (e.g., bladder, prostate)(FIGS. 7 and 9) were collected and analyzed for gemcitabine content. Theresults are illustrated in FIGS. 7-9. The results show that sustainedgemcitabine urine concentrations have been found to produce significantgemcitabine levels in bladder tissue, which are at or exceed therapeuticconcentrations based on in vitro bladder cancer cell experiments. Thegemcitabine levels in the bladder are shown in FIG. 9, which alsodepicts a significantly lower concentration of gemcitabine in thebladder 24 hours after a clinically relevant IV dose.

Similar and unexpected results have been observed in prostate tissue, asshown in FIG. 7. In particular, prostate gemcitabine tissueconcentrations are substantially higher than those observed after IVadministration. Furthermore, the absolute tissue levels are well abovethe concentrations shown to kill prostate cancer cells in vitro, whichrange from 10 ng/mL to 200 ng/mL.

In contrast, it is noted that Phase 2 clinical studies of gemcitabineprostate cancer patients have shown limited efficacy. It is also notedthat animal studies have shown liposomal formulations of gemcitabinedramatically enhance efficacy—which activity was thought to be theresult of improved tumor exposure, because (i) liposomes may protectgemcitabine from rapid metabolism, and (ii) liposomes may improvegemcitabine prostate tissue concentrations. Accordingly, in view of thepresent animal study, which shows the unexpected accumulation ofgemcitabine in prostate tissue following administration of gemcitabinein urine, it is believed that intravesical delivery of gemcitabine willproduce superior gemcitabine efficacy in prostate cancer withoutsignificant systemic exposure.

Example 2: Limited Prostate Uptake of Cisplatin and Oxaliplatin fromBladder

In a similar study to Example 1 oxaliplatin or cisplatin wereadministered to male Sprague Dawley rats by intra-urinary bladdercannula, over a 6- or 24-hour continuous perfusion, or by a single IVbolus. As shown in FIG. 10 and FIG. 11, oxaliplatin and cisplatinprostate partitioning, although achieving therapeutic bladderconcentrations and kidney concentrations following cisplatin, exhibitpoor partitioning into the prostate.

Publications cited herein and the materials for which they are cited arespecifically incorporated by reference. Modifications and variations ofthe methods and devices described herein will be obvious to thoseskilled in the art from the foregoing detailed description. Suchmodifications and variations are intended to come within the scope ofthe appended claims.

I claim:
 1. A medical device comprising: a housing configured for intravesical insertion; and a dosage form comprising gemcitabine, wherein the housing holds the dosage form and is configured to release the gemcitabine into a bladder of a patient at a mean average amount from 1 mg/day to about 300 mg/day to provide an amount therapeutically effective for treatment of prostate cancer.
 2. The device of claim 1, wherein the gemcitabine contained in the housing is in a non-liquid form.
 3. The device of claim 2, wherein the non-liquid form is selected from the group consisting of tablets, granules, semisolids, capsules, and combinations thereof.
 4. The device of claim 1, wherein the housing is elastically deformable between a retention shape configured to retain the device in the bladder and a deployment shape for passage of the device through a urethra of the patient.
 5. The device of claim 1, which is configured to release from 1 mg/day to 100 mg/day of the gemcitabine for up to 7 days.
 6. The device of claim 1, which is configured to release from 20 mg/day to 300 mg/day of the gemcitabine for up to 7 days.
 7. The device of claim 1, wherein the device is configured to continuously release the gemcitabine into urine in the bladder over a sustained period.
 8. The device of claim 7, wherein the sustained period is at least 2 hours.
 9. The device of claim 7, wherein the sustained period is from 1 day to 14 days.
 10. The device of claim 1, wherein the device is configured to release the gemcitabine to achieve a sustained concentration of the gemcitabine in urine in the bladder sufficient to produce a therapeutic concentration of the gemcitabine in a prostate of the patient.
 11. A medical device comprising: a housing configured for intravesical insertion; and a dosage form comprising gemcitabine, wherein the housing holds the dosage form and is configured to release the gemcitabine at a mean average amount from 1 mg/day to about 300 mg/day to provide an amount effective to achieve a sustained concentration of the gemcitabine in urine in a bladder of a patient, the amount being sufficient to produce a therapeutic concentration of the gemcitabine in a prostate of the patient for treatment of prostate cancer.
 12. The device of claim 11, wherein the gemcitabine contained in the housing is in a non-liquid form.
 13. The device of claim 12, wherein the non-liquid form is selected from the group consisting of tablets, granules, semisolids, capsules, and combinations thereof.
 14. The device of claim 11, wherein the housing is elastically deformable between a retention shape configured to retain the device in the bladder and a deployment shape for passage of the device through a urethra of the patient.
 15. The device of claim 11, which is configured to release from 1 mg/day to 100 mg/day of the gemcitabine for up to 7 days.
 16. The device of claim 11, which is configured to release from 20 mg/day to 300 mg/day of the gemcitabine for up to 7 days.
 17. The device of claim 11, wherein the device is configured to continuously release the gemcitabine into the urine in the bladder over a sustained period.
 18. The device of claim 17, wherein the sustained period is at least 2 hours.
 19. The device of claim 17, wherein the sustained period is from 1 day to 14 days. 